The role of the lymphatic system in the absorption and biodistribution of antitumor agents and monoclonal antibodies administered by IV and SC routes in normal and tumor-bearing rodents is under investigation. Following subcutaneous injection, monoclonal antibodies are delivered via lymphatic channels to regional lymph nodes. Initial studies in mice with monoclonal antibodies to murine histocompatibility antigens showed that over 50% of the dose absorbed from subcutaneous injection site bound specifically to cells in regional lymph nodes. Similar findings have now been obtained for monoclonal antibodies to B and T lymphocytes which may offer an alternative to radiocolloids in detecting gross abnormalities in lymphatic drainage and lymph node chains by lymphoscintigraphy. Study of in vitro binding characteristics combined with a variety of in vivo pharmacological parameters affecting lymphatic delivery of antibodies has enabled us to develop a firm quantitative understanding of the delivery process with the aid of computer modeling systems. Using this delivery system for a monoclonal antibody against guinea pig line 10 hepatocarcinoma, we have succeeded in detecting early metastatic tumor in lymph nodes of guinea pigs by gamma camera imaging. Attempts at therapy in the guinea pig model using antibody coupled to ricin toxin are currently in progress. Information obtained from studies in guinea pigs has been applied to detection of clinical stage II malignant melanoma and protocols for similar trials have been developed for breast cancer, non-small cell lung cancer and lymphoma.